severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Severe combined immunodeficiency due to adenosine deaminase deficiency is a rare, life-threatening inherited disorder in which the immune system cannot make working T, B, or natural killer cells. Without these cells, the body cannot fight everyday germs, so affected babies often develop serious, repeated infections within the first months of life. The problem is caused by changes in the ADA gene that stop production of an enzyme that protects young immune cells from toxic waste products. The severity and specific features can vary considerably from person to person, and some individuals show milder or later-onset symptoms. The condition occurs in about one to nine people out of every million and is passed down in an autosomal recessive pattern.

The hallmark feature is profound combined immunodeficiency, meaning that T cells, B cells, and natural killer (NK) cells are all severely reduced or absent. This leaves affected infants highly vulnerable to serious bacterial, viral, and fungal infections that recur or fail to resolve with routine treatment. Early clues often include persistent respiratory illnesses, chronic diarrhea, skin rashes such as eczema or widespread candidiasis, and recurrent fevers that do not respond as expected. Failure to thrive is common, and many children have motor delays because frequent illness limits normal development. Over time, complications can involve many organ systems. Chronic lung disease may develop from repeated infections, and some individuals experience heart murmurs such as pulmonic regurgitation. Laboratory testing frequently shows very low immunoglobulin levels, increased eosinophil counts, and undetectable lymph nodes or tonsils on examination. Autoimmune problems, including thyroid inflammation or allergic-type reactions, occur in a subset of patients. Not all individuals experience every feature, and severity varies considerably. Some people with partial ADA activity present later in childhood or even adulthood with a milder course, underscoring the broad clinical spectrum.

This condition is caused by pathogenic variants in the ADA gene, which provides instructions for making the enzyme adenosine deaminase. Without adequate enzyme activity, toxic by-products accumulate and destroy developing immune cells, leading to the severe lymphopenia that defines the disease. It is inherited in an autosomal recessive pattern. Individuals must receive one altered ADA gene from each parent to be affected. Parents who each carry one altered copy (carriers) are typically healthy but have a 25 percent chance with each pregnancy of having an affected child. The disorder is more common when parents share a common ancestor, because related individuals are more likely to carry the same rare genetic change. Carrier testing may be particularly helpful for extended family members who are planning children. Genetic counseling is strongly recommended for families to understand testing options, recurrence risks, and reproductive choices.

Currently, management focuses on restoring immune function, preventing infections, and monitoring for complications. Hematopoietic stem cell transplantation from a matched donor can re-establish a functioning immune system and is considered curative for many patients. When transplantation is not immediately possible, supportive measures such as protective isolation, antimicrobial prophylaxis, and immunoglobulin replacement therapy help reduce infection risk. Long-term management includes regular surveillance by a multidisciplinary team that typically involves immunologists, infectious disease specialists, pulmonologists, and nutrition experts. Ongoing monitoring of lymphocyte counts, immunoglobulin levels, growth, and organ function helps clinicians adjust care as needed and detect complications early. Additional approaches such as enzyme replacement or gene-based therapies are under investigation, but they are still considered experimental at this time. Families should discuss the full range of options with their care team to determine the most appropriate plan for their individual situation.

Without effective treatment, adenosine deaminase-related SCID is often fatal in early childhood because routine infections can become life-threatening. However, outcomes vary widely depending on the severity of enzyme deficiency, the age at diagnosis, and how quickly immune-restoring therapy is initiated. Children who receive early stem cell transplantation or comparable immune-reconstituting treatment can achieve robust immune function and lead active lives, although they may still require ongoing monitoring for late effects. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with immunology centers experienced in treating SCID, enroll in patient registries that track long-term health, and meet with a genetic counselor to plan for future pregnancies and extended family testing.